bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023‒08‒20
seventeen papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research

  1. Cell Rep. 2023 Aug 08. pii: S2211-1247(23)00951-8. [Epub ahead of print] 112940
      Interleukin (IL)-6 is abundantly expressed in the tumor microenvironment and is associated with poor patient outcomes. Here, we demonstrate that the deletion of the suppressor of cytokine signaling 3 (SOCS3) in T cells potentiates anti-tumor immune responses by conferring the anti-tumorigenic function of IL-6 in mouse and human models. In Socs3-deficient CD8+ T cells, IL-6 upregulates the expression of type I interferon (IFN)-regulated genes and enhances the anti-tumor effector function of T cells, while also modifying mitochondrial fitness to increase mitochondrial membrane potential and reactive oxygen species (ROS) levels and to promote metabolic glycolysis in the energy state. Furthermore, Socs3 deficiency reduces regulatory T cells and increases T helper 1 (Th1) cells. SOCS3 knockdown in human chimeric antigen receptor T (CAR-T) cells exhibits a strong anti-tumor response in humanized mice. Thus, genetic disruption of SOCS3 offers an avenue to improve the therapeutic efficacy of adoptive T cell therapy.
    Keywords:  CAR-T therapy; CP: Cancer; IL-6; anti-tumor immunity; cytotoxic T cell; effector T cells; mitochondrial fitness; regulatory T cells; suppressor of cytokine signaling 3
  2. Sci Immunol. 2023 Aug 25. 8(86): eade3369
      Identifying molecular mechanisms of exhausted CD8 T cells (Tex) is a key goal of improving immunotherapy of cancer and other diseases. However, high-throughput interrogation of in vivo Tex can be costly and inefficient. In vitro models of Tex are easily customizable and quickly generate high cellular yield, enabling CRISPR screening and other high-throughput assays. We established an in vitro model of chronic stimulation and benchmarked key phenotypic, functional, transcriptional, and epigenetic features against bona fide in vivo Tex. We leveraged this model of in vitro chronic stimulation in combination with CRISPR screening to identify transcriptional regulators of T cell exhaustion. This approach identified several transcription factors, including BHLHE40. In vitro and in vivo validation defined a role for BHLHE40 in regulating a key differentiation checkpoint between progenitor and intermediate Tex subsets. By developing and benchmarking an in vitro model of Tex, then applying high-throughput CRISPR screening, we demonstrate the utility of mechanistically annotated in vitro models of Tex.
  3. Front Immunol. 2023 ;14 1233870
      CD8+ lymphocytes are adaptive immunity cells with the particular function to directly kill the target cell following antigen recognition in the context of MHC class I. In addition, CD8+ T cells may release pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), and a plethora of other cytokines and chemoattractants modulating immune and inflammatory responses. A role for CD8+ T cells has been suggested in aging and several diseases of the central nervous system (CNS), including Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, limbic encephalitis-induced temporal lobe epilepsy and Susac syndrome. Here we discuss the phenotypic and functional alterations of CD8+ T cell compartment during these conditions, highlighting similarities and differences between CNS disorders. Particularly, we describe the pathological changes in CD8+ T cell memory phenotypes emphasizing the role of senescence and exhaustion in promoting neuroinflammation and neurodegeneration. We also discuss the relevance of trafficking molecules such as selectins, mucins and integrins controlling the extravasation of CD8+ T cells into the CNS and promoting disease development. Finally, we discuss how CD8+ T cells may induce CNS tissue damage leading to neurodegeneration and suggest that targeting detrimental CD8+ T cells functions may have therapeutic effect in CNS disorders.
    Keywords:  CD8+ T lymphocytes; cytotoxicity; neurodegenerative diseases; neurotoxicity; tissue resident memory CD8+ T cells
  4. Nat Immunol. 2023 Aug 17.
      In development, pioneer transcription factors access silent chromatin to reveal lineage-specific gene programs. The structured DNA-binding domains of pioneer factors have been well characterized, but whether and how intrinsically disordered regions affect chromatin and control cell fate is unclear. Here, we report that deletion of an intrinsically disordered region of the pioneer factor TCF-1 (termed L1) leads to an early developmental block in T cells. The few T cells that develop from progenitors expressing TCF-1 lacking L1 exhibit lineage infidelity distinct from the lineage diversion of TCF-1-deficient cells. Mechanistically, L1 is required for activation of T cell genes and repression of GATA2-driven genes, normally reserved to the mast cell and dendritic cell lineages. Underlying this lineage diversion, L1 mediates binding of TCF-1 to its earliest target genes, which are subject to repression as T cells develop. These data suggest that the intrinsically disordered N terminus of TCF-1 maintains T cell lineage fidelity.
  5. Cell Mol Immunol. 2023 Aug 15.
      CD8+ T cells are the key executioners of the adaptive immune arm, which mediates antitumor and antiviral immunity. Naïve CD8+ T cells develop in the thymus and are quickly activated in the periphery after encountering a cognate antigen, which induces these cells to proliferate and differentiate into effector cells that fight the initial infection. Simultaneously, a fraction of these cells become long-lived memory CD8+ T cells that combat future infections. Notably, the generation and maintenance of memory cells is profoundly affected by various in vivo conditions, such as the mode of primary activation (e.g., acute vs. chronic immunization) or fluctuations in host metabolic, inflammatory, or aging factors. Therefore, many T cells may be lost or become exhausted and no longer functional. Complicated intracellular signaling pathways, transcription factors, epigenetic modifications, and metabolic processes are involved in this process. Therefore, understanding the cellular and molecular basis for the generation and fate of memory and exhausted CD8+ cells is central for harnessing cellular immunity. In this review, we focus on mammalian target of rapamycin (mTOR), particularly signaling mediated by mTOR complex (mTORC) 2 in memory and exhausted CD8+ T cells at the molecular level.
    Keywords:  CD8+ T cell; Sin1; T-cell exhaustion; T-cell memory; mTOR
  6. Geroscience. 2023 Aug 18.
      A progressive decline in biological function and fitness is, generally, how aging is defined. However, in 2013, a description on the "hallmarks of aging" in mammals was published, and within it, it described biological processes that are known to alter the aging phenotype. These include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication (inflammation), and changes within the microbiome. This mini-review provides a detailed account of the progress on each of these hallmarks of aging in the domestic dog within the last 5 years. Additionally, when there are gaps in the literature between other mammalian species and dogs, I highlight the aging biomarkers that may be missing for dogs as aging models. I also argue for the importance of dog aging studies to include several breeds of dogs at differing ages and for age corrections for breeds with differing mean lifespans throughout.
    Keywords:  Altered intercellular communication; Cellular senescence; Deregulated nutrient sensing; Dog aging; Epigenetic alterations; Genomic instability; Inflammaging; Loss of proteostasis; Microbiome; Mitochondrial dysfunction; Stem cell exhaustion; Telomere attrition
  7. Immunopharmacol Immunotoxicol. 2023 Aug 15. 1-11
      BACKGROUND: Due to the increase of the elderly's population and related social and economic problems, it is very important to provide strategies on health. In this regard, induction of T lymphocytes responses, the most important cells of the immune system, may be a good approach. Among different agents considered as antiaging factors, mTORC1 pathway inhibitors are significant. So, the purpose of this study was to evaluate the effect of two mTORC1 inhibitors, Everolimus and Metformin, on age-related features of activated T cells.MATERIALS AND METHODS: Optimum doses of drugs was determined with evaluating the effect of treatments on IL-2 gene expression. T cells isolated from old and young mice were treated with drugs and PHA. IL-2 production was evaluated by ELISA. Also, the expression of CD28, PD-1, and KLRG-1, proliferation, and intracellular oxidative stress were assessed by flow cytometry-based assays, phenotyping, CFSE, and DCF-DA assay respectively.
    RESULTS: Both drugs increased IL-2 production in the T cells of old mice. Also, using drugs especially Metformin could improve age-related phenotypical markers and increase the proliferation of T cells of old mice significantly. In addition, Metformin and Everolimus reduced intracellular oxidative stress in aged cells. However, the effect of both drugs on the T cells of young mice wasn't significant or was in opposite to the results of old mice T cells.
    DISCUSSION: In line with studies noting mTOR inhibitors as antiaging drugs, Metformin and Everolimus may improve T cells affected from aging in vitro, and a decrease in intracellular oxidative stress may be one of their mechanism of function.
    Keywords:  Aging; T cell; everolimus; mTORC1; metformin
  8. Oncoimmunology. 2023 ;12(1): 2244330
      Malignant tumors often escape anticancer immune surveillance by suppressing the cytotoxic functions of T lymphocytes. While many of these immune evasion networks include checkpoint proteins, small molecular weight compounds, such as the amino acid L-kynurenine (LKU), could also substantially contribute to the suppression of anti-cancer immunity. However, the biochemical mechanisms underlying the suppressive effects of LKU on T-cells remain unclear. Here, we report for the first time that LKU suppresses T cell function as an aryl hydrocarbon receptor (AhR) ligand. The presence of LKU in T cells is associated with AhR activation, which results in competition between AhR and hypoxia-inducible factor 1 alpha (HIF-1α) for the AhR nuclear translocator, ARNT, leading to T cell exhaustion. The expression of indoleamine 2,3-dioxygenase 1 (IDO1, the enzyme that leads to LKU generation) is induced by the TGF-β-Smad-3 pathway. We also show that IDO-negative cancers utilize an alternative route for LKU production via the endogenous inflammatory mediator, the high mobility group box 1 (HMGB-1)-interferon-gamma (IFN-γ) axis. In addition, other IDO-negative tumors (like T-cell lymphomas) trigger IDO1 activation in eosinophils present in the tumor microenvironment (TME). These mechanisms suppress cytotoxic T cell function, and thus support the tumor immune evasion machinery.
    Keywords:  T cells; cancer; immune checkpoints; immune escape; kynurenine
  9. bioRxiv. 2023 Aug 04. pii: 2023.08.02.551712. [Epub ahead of print]
      Lactate has long been considered a cellular waste product. However, we found that as extracellular lactate accumulates, it also enters the mitochondrial matrix and stimulates mitochondrial electron transport chain (ETC) activity. The resulting increase in mitochondrial ATP synthesis suppresses glycolysis and increases the utilization of pyruvate and/or alternative respiratory substrates. The ability of lactate to increase oxidative phosphorylation does not depend on its metabolism. Both L- and D-lactate are effective at enhancing ETC activity and suppressing glycolysis. Furthermore, the selective induction of mitochondrial oxidative phosphorylation by unmetabolized D-lactate reversibly suppressed aerobic glycolysis in both cancer cell lines and proliferating primary cells in an ATP-dependent manner and enabled cell growth on respiratory-dependent bioenergetic substrates. In primary T cells, D-lactate enhanced cell proliferation and effector function. Together, these findings demonstrate that lactate is a critical regulator of the ability of mitochondrial oxidative phosphorylation to suppress glucose fermentation.
  10. JCI Insight. 2023 Aug 15. pii: e169308. [Epub ahead of print]
      Glutaminolysis is a hallmark of the activation and metabolic reprogramming of T cells. Isotopic tracer analyses of antigen-activated effector CD8+ T cells revealed that glutamine is the principal carbon source for the biosynthesis of polyamines putrescine, spermidine and spermine. These metabolites play critical roles in activation-induced T-cell proliferation, as well as for the production of hypusine, which is derived from spermidine and is covalently linked to the translation elongation factor eIF5A. Here, we demonstrated that the glutamine-polyamine-hypusine axis controls the expression of CD69, an important regulator of tissue resident memory T cells (TRM). Inhibition of this circuit augmented the development of TRM cells ex vivo and in vivo in the bone marrow, a well-established niche for TRM cells. Furthermore, blocking the polyamine-hypusine axis augmented CD69 expression and IFN-γ and TNF-α production in human CD8+ T cells from peripheral blood and sarcoma tumor infiltrating lymphocytes, as well as in human CD8+ CAR-T cells. Collectively, these findings support the notion that the polyamine-hypusine circuit can be exploited to modulate TRM cells for therapeutic benefit.
    Keywords:  Immunology; Metabolism; Polyamines; T cells
  11. J Cell Sci. 2023 Aug 15. pii: jcs260607. [Epub ahead of print]136(16):
      Bioenergetic metabolism is a key regulator of cellular function and signaling, but how it can instruct the behavior of cells and their fate during embryonic development remains largely unknown. Here, we investigated the role of glucose metabolism in the development of avian trunk neural crest cells (NCCs), a migratory stem cell population of the vertebrate embryo. We uncovered that trunk NCCs display glucose oxidation as a prominent metabolic phenotype, in contrast to what is seen for cranial NCCs, which instead rely on aerobic glycolysis. In addition, only one pathway downstream of glucose uptake is not sufficient for trunk NCC development. Indeed, glycolysis, mitochondrial respiration and the pentose phosphate pathway are all mobilized and integrated for the coordinated execution of diverse cellular programs, epithelial-to-mesenchymal transition, adhesion, locomotion, proliferation and differentiation, through regulation of specific gene expression. In the absence of glucose, the OXPHOS pathway fueled by pyruvate failed to promote trunk NCC adaptation to environmental stiffness, stemness maintenance and fate-decision making. These findings highlight the need for trunk NCCs to make the most of the glucose pathway potential to meet the high metabolic demands appropriate for their development.
    Keywords:  Bioenergetics; Cell migration; Fate decision; Glycolysis; Neural crest; Oxidative phosphorylation
  12. Cell Rep Med. 2023 Aug 09. pii: S2666-3791(23)00310-5. [Epub ahead of print] 101157
      To evaluate whether nicotinamide adenine dinucleotide-positive (NAD+) boosting modulates adaptive immunity, primary CD4+ T cells from healthy control and psoriasis subjects were exposed to vehicle or nicotinamide riboside (NR) supplementation. NR blunts interferon γ (IFNγ) and interleukin (IL)-17 secretion with greater effects on T helper (Th) 17 polarization. RNA sequencing (RNA-seq) analysis implicates NR blunting of sequestosome 1 (sqstm1/p62)-coupled oxidative stress. NR administration increases sqstm1 and reduces reactive oxygen species (ROS) levels. Furthermore, NR activates nuclear factor erythroid 2-related factor 2 (Nrf2), and genetic knockdown of nrf2 and the Nrf2-dependent gene, sqstm1, diminishes NR amelioratory effects. Metabolomics analysis identifies that NAD+ boosting increases arginine and fumarate biosynthesis, and genetic knockdown of argininosuccinate lyase ameliorates NR effects on IL-17 production. Hence NR via amino acid metabolites orchestrates Nrf2 activation, augments CD4+ T cell antioxidant defenses, and attenuates Th17 responsiveness. Oral NR supplementation in healthy volunteers similarly increases serum arginine, sqstm1, and antioxidant enzyme gene expression and blunts Th17 immune responsiveness, supporting evaluation of NAD+ boosting in CD4+ T cell-linked inflammation.
    Keywords:  CD4(+) T cell; NAD(+) boosting; Th17 cell; arginine biosynthesis; nicotinamide riboside; nrf2; psoriasis
  13. Cell Rep Med. 2023 Aug 15. pii: S2666-3791(23)00307-5. [Epub ahead of print]4(8): 101154
      Strategies to increase intratumoral concentrations of an anticancer agent are desirable to optimize its therapeutic potential when said agent is efficacious primarily within a tumor but also have significant systemic side effects. Here, we generate a bifunctional protein by fusing interleukin-10 (IL-10) to a colony-stimulating factor-1 receptor (CSF-1R)-blocking antibody. The fusion protein demonstrates significant antitumor activity in multiple cancer models, especially head and neck cancer. Moreover, this bifunctional protein not only leads to the anticipated reduction in tumor-associated macrophages but also triggers proliferation, activation, and metabolic reprogramming of CD8+ T cells. Furthermore, it extends the clonotype diversity of tumor-infiltrated T cells and shifts the tumor microenvironment (TME) to an immune-active state. This study suggests an efficient strategy for designing immunotherapeutic agents by fusing a potent immunostimulatory molecule to an antibody targeting TME-enriched factors.
    Keywords:  CD8 T cell; TCR repertoire; colony-stimulating factor 1-receptor; head and neck cancer; immunotherapy; interleukin-10; macrophage; tumor microenvironment
  14. J Immunother Cancer. 2023 08;pii: e007114. [Epub ahead of print]11(8):
      BACKGROUND: CD8+ T cells are a highly diverse population of cells with distinct phenotypic functions that can influence immunotherapy outcomes. Further insights on the roles of CD8+ specificities and TCR avidity of naturally arising tumor-specific T cells, where both high and low avidity T cells recognizing the same peptide-major histocompatibility complex (pMHC) coexist in the same tumor, are crucial for understanding T cell exhaustion and resistance to PD-1 immunotherapy.METHODS: CT26 models were treated with anti-PD-1 on days 3, 6 and 9 following subcutaneous tumor implantation generating variable responses during early tumor development. Tetramer staining was performed to determine the frequency and avidity of CD8+ T cells targeting the tumor-specific epitope GSW11 and confirmed with tetramer competition assays. Functional characterization of high and low avidity GSW11-specific CD8+ T cells was conducted using flow cytometry and bulk RNA-seq. In vitro cytotoxicity assays and in vivo adoptive transfer experiments were performed to determine the cytotoxicity of high and low avidity populations.
    RESULTS: Treatment success with anti-PD-1 was associated with the preferential expansion of low avidity (Tetlo) GSW11-specific CD8+ T cells with Vβ TCR expressing clonotypes. High avidity T cells (Tethi), if present, were only found in progressing PD-1 refractory tumors. Tetlo demonstrated precursor exhausted or progenitor T cell phenotypes marked by higher expression of Tcf-1 and T-bet, and lower expression of the exhaustion markers CD39, PD-1 and Eomes compared with Tethi, whereas Tethi cells were terminally exhausted. Transcriptomics analyses showed pathways related to TCR signaling, cytotoxicity and oxidative phosphorylation were significantly enriched in Tetlo found in both regressing and progressing tumors compared with Tethi, whereas genes related to DNA damage, apoptosis and autophagy were downregulated. In vitro studies showed that Tetlo exhibits higher cytotoxicity than Tethi. Adoptive transfer of Tetlo showed more effective tumor control than Tethi, and curative responses were achieved when Tetlo was combined with two doses of anti-PD-1.
    CONCLUSIONS: Targeting subdominant T cell responses with lower avidity against pMHC affinity neoepitopes showed potential for improving PD-1 immunotherapy. Future interventions may consider expanding low avidity populations via vaccination or adoptive transfer.
    Keywords:  Antigen Presentation; Antigens, Neoplasm; Immune Checkpoint Inhibitors; Immune Tolerance; Lymphocytes, Tumor-Infiltrating
  15. Nat Immunol. 2023 Aug 14.
      Omnivorous animals, including mice and humans, tend to prefer energy-dense nutrients rich in fat over plant-based diets, especially for short periods of time, but the health consequences of this short-term consumption of energy-dense nutrients are unclear. Here, we show that short-term reiterative switching to 'feast diets', mimicking our social eating behavior, breaches the potential buffering effect of the intestinal microbiota and reorganizes the immunological architecture of mucosa-associated lymphoid tissues. The first dietary switch was sufficient to induce transient mucosal immune depression and suppress systemic immunity, leading to higher susceptibility to Salmonella enterica serovar Typhimurium and Listeria monocytogenes infections. The ability to respond to antigenic challenges with a model antigen was also impaired. These observations could be explained by a reduction of CD4+ T cell metabolic fitness and cytokine production due to impaired mTOR activity in response to reduced microbial provision of fiber metabolites. Reintroducing dietary fiber rewired T cell metabolism and restored mucosal and systemic CD4+ T cell functions and immunity. Finally, dietary intervention with human volunteers confirmed the effect of short-term dietary switches on human CD4+ T cell functionality. Therefore, short-term nutritional changes cause a transient depression of mucosal and systemic immunity, creating a window of opportunity for pathogenic infection.
  16. Semin Immunol. 2023 Aug 10. pii: S1044-5323(23)00108-2. [Epub ahead of print]70 101817
      The secondary lymphoid organs (SLOs) undergo structural changes with age, which correlates with diminishing immune responses against infectious disease. A growing body of research suggests that the aged tissue microenvironment can contribute to decreased immune function, independent of intrinsic changes to hematopoietic cells with age. Stromal cells impart structural integrity, facilitate fluid transport, and provide chemokine and cytokine signals that are essential for immune homeostasis. Mechanisms that drive SLO development have been described, but their roles in SLO maintenance with advanced age are unknown. Disorganization of the fibroblasts of the T cell and B cell zones may reduce the maintenance of naïve lymphocytes and delay immune activation. Reduced lymphatic transport efficiency with age can also delay the onset of the adaptive immune response. This review focuses on recent studies that describe age-associated changes to the stroma of the lymph nodes and spleen. We also review recent investigations into stromal cell biology, which include high-dimensional analysis of the stromal cell transcriptome and viscoelastic testing of lymph node mechanical properties, as they constitute an important framework for understanding aging of the lymphoid tissues.
    Keywords:  Aging; Endothelium; Fibroblast; Lymphatics; Stroma; Tissue microenvironment